We have developed a new mouse model that demonstrates that the sex of a litter carried by a mouse dam can affect social behavior and sensorimotor processing in her subsequent offspring. Mouse dams are implanted with a litter of all male embryos or a litter of all female embryos and allowed to carry this first litter to term and wean the offspring. The dams are then mated to produce a second litter consisting of both sexes. We find that males in the second generation display differences in behavior depending on whether all their older siblings were brothers or sisters. Many of these behavioral differences are reminiscent of autism spectrum disorder in humans. Compared to male mice with older sisters, male mice with older brothers display an exaggerated startle response, inappropriate social interactions, avoidance of novel objects, and difficulty in auditory processing. Each of these behaviors represent an important component of autism spectrum disorder in humans. Thus we may have stumbled upon a previously unsuspected risk factor for autism in males: the number of older brothers. In addition, the effect of older brothers on the development of subsequent brothers may represent a contributing factor to the greater incidence of other neurodevelopmental disorders, such as ADD and dyslexia, in boys than in girls. We would like to explore our mouse model for this "fraternal birth order" (FBO) effect. Understanding how older brothers affect behaviors in our mice may shed light on how other factors (including genes and toxin) might lead to neurodevelopmental disorders in humans. We will investigate possible mechanisms that might underlie these phenomena, including the possibility that the maternal immune system may be directing antibodies to male-specific antigens in subsequent sons, and that maternal experience caring for pups of one sex may affect subsequent maternal care of subsequent sons. PUBLIC HEALTH RELEVANCE We will investigate a mouse model for the effects of older brothers on behaviors that typify autistic spectrum disorder. Preliminary evidence suggests that a mammalian mother that has carried a son to term may produce antibodies that attack the nervous system of subsequent sons in utero. By learning how older brothers increase autistic-like behaviors in mice, we may gain insight into the development of autism and possible therapies for this disorder. [unreadable] [unreadable] [unreadable]